The most common neurodegenerative pathologies underlying age associated cognitive decline, mild cognitive impairment (MCI) and dementia are Alzheimer's disease (AD) and Lewy body disease (LBD) pathologies. Evidence from proton MR Spectroscopy (MRS) and diffusion tensor MRI (DTI) suggest that these techniques are sensitive to early events in the neurodegenerative disease process at the cellular or molecular level. These MR markers may be more sensitive to degenerative changes preceding atrophy, and may provide additional information over structural MRI especially early in the disease course. Although the recent findings in clinically diagnosed patients are promising, the pathologic underpinnings of MRS and DTI alterations in neurodegenerative dementia are not well understood. Our goal is to validate MRS and DTI measures as surrogate markers of AD and LBD pathologies, because they are the most common neurodegenerative changes found in the elderly population. Our objective is to identify the biological correlates of antemortem MRS and DTI changes in specific cortical regions and white matter tracts associated with the paired helical filament (PHF)-tau, amyloid-[unreadable] and alpha-synuclein mediated pathology. The overarching goal is to translate the MR markers into clinically valid measures of AD and LBD pathologies. The antemortem MRS and DTI changes associated with postmortem PHF-tau, amyloid-b and alpha-synuclein mediated neurodegenerative pathology will be identified using ROI-based quantitative methods for correlating antemortem imaging with postmortem histology. Finally, we will translate MRS and DTI markers to clinically valid measures of pathological severity. PUBLIC HEALTH RELEVANCE: As an outcome of the proposed investigations, we will identify the pathologic basis of magnetic resonance spectroscopy and diffusion tensor imaging changes associated with neurodegeneration in a spectrum of Alzheimer's disease and Lewy body disease pathologies. The proposal is relevant because, with the development of disease modifying treatments, imaging markers of neurodegenerative dementia pathologies will be required for early diagnosis, treatment decisions and monitoring treatment response.